ES2281312T3 - NEW SYNTHESIS OF IRBESARTAN. - Google Patents

Abstract

The present invention provides a process for preparing irbesartan.

Description

New synthesis of irbesartan.

Background of the invention

Irbesartan is a known antagonist (blocker) of the angiotensin II receptor. Angiotensin is an important participant in the system renin-agiotensin-aldosterone (RAAS) and has a great influence on blood pressure. The structure of irbesartan is represented below (I)

one

The synthesis of ibesartan is exposed, among others things, in US Patent Nos. 5,270,317 and No. 5,559,233, both fully incorporated herein as reference. In the synthesis described therein, the before the last stage of reaction (excluding stimulation and purification) involves the reaction of a cyano group in the ring biphenyl with an azide, for example tributyltin azide. Be It will require a reaction time of 210 hours. See for example the US Patent No. 5,270,317.

US Patent No. 5,629,331 also discloses a synthesis of irbesartan from a precursor 2-n-butyl-3 - [(2'-cyanobiphenyl-4-yl) methyl] -1,3-diazaspiro [4.4] non-1-eno-4-one  with sodium azide using a bipolar aprotic solvent. How I know recognized in US Patent No. 5,629,331, there are risks of safety involved in the use of azides (column 4, line 39). Also, bipolar aprotic solvents (for example methylpyrrolidone) have a relatively boiling point high and can be difficult to eliminate.

Document FR278043 discloses a procedure in which irbesartan is prepared by reaction of 2-n-butyl-4-spirocyclopentane-2-imidazoline-5-one  with 4-bromomethyl-2-cyanobiphenyl, followed by reaction of the cyano intermediate substituted with azide of Tributyltin in xylene for 66 hours to produce the derivative corresponding tetrazolyl substituted, which is hydrolyzed to form irbesartan with a total yield of approximately 42%. The procedure involves two independent stages of purification chromatographic

The synthesis of other angiotensin II receptor antagonist analogs is described in GB2281072, Murugesan, N., et al ., J. Med. Chem. 2002, 45, 3829-3835, EP0508393 and EP0782996.

There is a need for a synthetic route Improved for Irbesartan.

Summary of the invention

In one aspect, the present invention relates to to a preparation procedure for 2-butyl-3 - [[2 '- (1-trityl-1H-tetrazol-5-yl) biphen-4-yl] methyl] 1,3-diazaspiro [4.4] non-1-eno-4-one  (IRB-03) including the reaction steps of 2-butyl-3- (4'-bromobenzyl) -1,3-diazaspiro [4.4] non-1-eno-4-one  (IRB-05) with the acid 2- (1-Trityl-1H-tetrazol-5-yl) phenylboronic (IRB-07) in the presence of a first solvent, especially tetrahydrofuran (THF) or dimethoxyethane, a second solvent, especially water, particularly combined with a base, and a catalyst that especially includes a complex of palladium for example Pd (O (O) CCH 3) 2 and a phosphine, especially a triarylphosphine, for example, triphenylphosphine (PPh_ {2}).

In another aspect, the present invention is refers to a process for preparing for example a compound from 3- (bromobenzyl) -1,3-diazaspiro [4.4] non-1-eno-4-one, especially 3- (4'-bromobenzyl) -1,3-diazaspiro [4.4] non-1-eno-4-one,  including the reaction step (combination), in the presence of a phase transfer catalyst (for example sulfate tetrabutylammonium), an acid addition salt, especially a hydrochloride, of 1,3-diazaspiro [4.4] non-1-eno-4-one  with a bromobenzyl halide compound (for example, 4-bromobenzyl), in a solvent system that includes a first solvent, especially a hydrocarbon aromatic, and a second solvent, especially brine that It contains a base.

In another aspect, the present invention is refers to the compound 2-butyl-3- (4'-bromobenzyl) -1,3-diazaspiro [4.4] non-1-eno-1-one,  especially when prepared according to the procedure previous.

Still in another aspect, the present invention refers to a process of preparing a compound of 5-phenyl-1-trityl-1H-tetrazol which includes the reaction stage of 5-phenyl-1H-tetrazol with chlorotriphenylmethane (trityl chloride) in a solvent, especially tetrahydrofuran, in the presence of a base, especially triethylamine.

Still in another aspect, the present invention refers to an acid preparation procedure 2- (tetrazol-5-yl) phenylboronic  which includes the stage that involves reacting the 5-phenyl-1-trityl-1H-tetrazol with a borate, especially a trialkyl borate (for example, tri-isopropyl borate) in a solvent, especially tetrahydrofuran, and in the presence of a base, especially n-butyllithium.

Even still in another aspect, the present invention relates to a method of preparing irbesartan  which includes the reaction stage of 2-butyl-3- (4'-bromobenzyl) -1,3-diazaspiro [4.4] nin-1-eno-4-one with the acid 2- (1-Trityl-1H-tetrazol-5-yl) phenylboronic in a two phase solvent system that has a first solvent, especially THF or dimethoxyethane or a mixture thereof, and a second solvent, especially water, in the presence of a catalyst, especially a palladium complex or a complex of nickel.

In another aspect, the present invention is refers to an irbesartan preparation procedure that includes the reaction step of an acid addition salt, especially the hydrochloride of 2-butyl-1,3-diazaspiro [4.4] non-1-eno-4-one  with bromobenzyl halide, especially bromide 4-bromobenzyl in the presence of a base, especially KOH or NaOH, in the presence of a solvent system of two phases with a first solvent, especially toluene, and a second solvent, especially water or brine.

Detailed description of the invention

The present invention provides a new synthesis of irbesartan and analogs thereof, including the reaction step of a 2- (5-tetrazoyl) phenylboronic acid with a 3- (bromobenzyl) -1,3-diazaspiro [4.4] non-1- eno-4-one. The step is carried out in the presence of a palladium or nickel catalyst. Said synthesis stage is known by any person skilled in the art as Suzuki coupling reaction. See, for example, N. Miyaura et al ., Tetrahedron Letters 1979, 3437. See also, N. Miyaura, A. Suzuki, Chem. Commun. 1979, 866. The step can be carried out in a two phase reaction system with the first and second liquid phases.

The first and second phases include the first and second solvents, respectively, which are substantially immiscible with each other so that, when combined in a glass of reaction, a two phase system is formed. The solvents are substantially immiscible with each other when mixing volumes equal to them, a two-phase system is formed in which the Volume of the two phases is essentially the same. Preferably substantially immiscible solvents are soluble in each other in the proportion of about 1% (by weight) or less.

The first solvents are solvents organic Examples of preferred organic solvents include, but are not limited to: ethereal solvents such as 1,2-dimethoxyethane (DME), diethoxymethane, (glymes) and tetrahydrofuran (THF); formal such as diethyl formal; Y hydrocarbon solvents such as toluene, m-xylene, o-xylene, the tetralins; Y mixtures of any of the above. Other useful hydrocarbons as first solvents in the practice of the present invention will be apparent to the person skilled in the art. The formal Preferred is diethyl formal. He 1,2-dimethoxyethane (DME) is the preferred glyme and It is particularly preferred as the first ether solvent, especially in combination with THF when the catalyst includes A palladium complex.

The second solvent may be water, or, preferably, an inorganic base combined with water. When use an inorganic base, the preferred inorganic base is the potassium carbonate Potassium hydroxide and sodium hydroxide are other examples of inorganic bases.

The new synthesis of irbesartan, and the analogues thereof, of the present invention includes the step consisting in reacting an acid 2- (5-tetrazoyl) phenylboronic (for example, tritilado) protected with a 3-Bromobenzyl-1,3-diazaspiro [4.4] non-1-eno-4-one.  A 2- (5-tetrazoyl) phenylboric acid preferred is acid 2- (5- (1-Trityl-1H-tetrazol)) phenylboric (IRB-07), Structure II. A 3-Bromobenzyl-1,3-diazaspiro [4.4] non-1-eno-3-4-one is the 2-butyl-3- (4'-bromobenzyl) -1,3-diazaspiro [4.4] non-1-eno-3-one  (IRB-05), Structure III.

2

The stage is performed in a reaction system of two phases that have the first and second liquid phases.

A catalyst is combined with the first phase liquid, preferably including an ethereal solvent. May used any known catalyst for the reaction of Suzuki Preferably, the catalyst is selected from among the palladium and nickel complexes. Most catalysts preferred include Pd (O (O) CCH 3) 2, PdCl 2 and NiCl2. When using a palladium complex such as Pd (O (O) CCH 3) 2 [for example PdOAc2], the catalyst also includes a triarylphosphine, especially triphenylphosphine. When the catalyst includes a palladium complex, the first solvent preferably includes a ethereal solvent, such as DME, which can form a complex with P.S.

As described above, the first phase liquid is an organic solvent phase, more preferably and specifically when the catalyst includes a complex of palladium, the first liquid phase is a mixture of 1,2-dimethoxyethane and THF. The relationship of 1,2-dimethoxyethane: THF can be from about 10: 1 to about 1: 5, the most ratio Preferred 1,2-diemethoxyethane: THF is about 6: 1 to about 2: 1. The reaction is carried out. in the presence of a catalyst.

Then IRB-07 will Combine with the solvent mixture. Water is added, a base and IRB-05, preferably successively, to the mixture of reaction, and a two-phase reaction system is formed that it has a first phase of organic solvent and a second phase watery The reaction mixture is heated under reflux conditions. for a reaction time of between 2 and 4 hours.

After the reaction time, the mixture of The reaction is allowed to cool, and the two phases are separated. If desired, the aqueous phase can be extracted one or more times with toluene and the extract (s) combined with the first phase (aromatic hydrocarbon). The first phase evaporates to obtain the raw residue of the IRB-03 product.

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3

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In the embodiments in which the acid 2- (1-Trityl-1H-tetrazol-5-yl) phenylboronic (IRB-07), is phenylboronic acid, the synthesis process of the present invention can and preferably it includes one more stage in which the trityl group is cleaves the tetrazole ring to produce irbesartan (IRB-00), or an analogue thereof. Raw waste produced in the synthesis stage described above dissolves  in a suitable solvent miscible in water. A solvent is miscible in water if miscible with water at least in any ratio from 80:20 to 20:80 (by weight). Acetone is a Water miscible solvent preferred. The resulting solution is acidify and stir at a temperature between about 15 ° C and approximately 30 ° C. The cleavage reaction time may conveniently controlled using layer chromatography fine. The acid is neutralized with a molar excess of base, preferably aqueous KOH or NaOH, and the water miscible solvent evaporates, preferably under reduced pressure. Alcohol is separated trityl formed and the liquid phase is acidified (for example, at a pH of about 4), preferably with mineral acid, plus preferably with HCl or H2SO4. The resulting suspension it is cooled and the product is recovered, for example, by filtration. If desired, the isolated product can be washed with a solvent organic, preferably a lower aliphatic alcohol, more preferably isopropanol or butanol, and dry, preferably at reduced pressure

Acid 2- (5-tetrazoyl) phenylboronic and 1,3-diazaspiro [4.4] non-1-eno-3- (bromobenzyl) -4-one which is reacted in the process of the present invention to produce irbesartan or an analogue thereof, it can be prepared by procedures known in the art or by following synthesis procedures.

Acid 2- (tetrazol-5-yl) phenylboronic can be prepared first by reacting a 5-phenyl-1H-tetrazol with chlorotriphenylmethane in the presence of a base, especially a amine (for example, triethylamine) in a solvent system suitable to provide a 5-phenyl-1-trityl-1H-tetrazole. A 5-phenyl-1-trityl-1H-tetrazol  preferred is IRB-08 (structure represented in the examples). Suitable solvents for the solvent system includes organic solvents. A solvent system Particularly preferred is a mixture of THF and triethylamine as base. After the elimination of the by-products, it can be isolated he 5-phenyl-1-trityl-1H-tetrazole,  such as IRB-06, before being used in the stage following the synthesis or used as a solution. He protected tetrazole thus formed is then reacted with a suitable borate in the presence of a base, to form the derivative of the desired boronic acid, such as acid 2- (1-Trityl-1H-tetrazol-5-yl) phenylboronic  (IRB-07; structure represented in the Examples). The reaction is carried out in solution, preferably in a organic solvent The organic solvent is more preferably THF. The appropriate basis will be apparent to the expert in The matter. A preferred base is butyllithium. The Preparation can be at any suitable temperature, preferably at a temperature below -20 ° C. The reaction is allowed to continue for a time that the expert in the matter you will know why it is adjusted according to the temperature of reaction.

The 3-Bromobenzyl-1,3-diazaspiro [4.4] non-1-eno-4-one can be prepared by combining an acid addition salt 1,3-diazaspiro [4.4] non-1-eno-4-one, preferably a hydrocarbon salt, with a halide of Bromobenzyl An acid addition salt of 1,3-diazaspiro [4.4] non-1-eno-4-one preferred is the hydrochloride of 2-butyl-1,3-diazaspiro [4.4] non-1-eno-4-one (IRB-01). A preferred bromobenzyl halide is the 4-bromobenzyl bromide. The reaction of hydrochloride 2-butyl-1,3-diazaspiro [4.4] non-1-eno-4-one (IRB-01) with bromide 4-Bromobenzyl leads to the production of 2-butyl-3- (4'-bromobenzyl) 1,3-diazaspiro [4.4] non-1-eno-4-one  (IRB-05). The 2-butyl-1,3-diazaspiro [4.4] non-1-eno-4-one is known in the field and is disclosed, for example, in the US Patent No. 5,559,233, which is incorporated herein as reference.

The reaction is carried out in a system of two phase reaction that has a first and a second phase liquid

A first liquid phase is prepared that comprises bromobenzyl halide and a catalyst of phase transfer in a suitable solvent. Solvent It can be an organic solvent. A more preferred solvent is the Toluene.

The phase transfer catalysts are well known to an expert in the field of organic synthesis. Phase transfer catalysts are especially useful when at least some first and second compounds that have to react with each other have these solubility characteristics different that there is no practical common solvent for them and, consequently, that combines a solvent of one of them with one solvent of the other one results in a system of two phases

Typically, when such compounds are due react, the first reagent dissolves in a first solvent and the second reagent dissolves in a second solvent Because the solvent of the first reagent is essentially insoluble in the solvent of the second reagent, it it forms a two-phase system and the reaction occurs in the interface between the two phases. The speed of said reaction interfacial can be greatly increased by using of a phase transfer catalyst (PTC).

Several classes of compounds are known that they can act as phase transfer catalysts, by example quaternary ammonium compounds and compounds of phosphonium, to mention only two. Bisulfate Tetrabutylammonium is a preferred PTC for use in the implementation of the present invention.

A second liquid phase comprising a salt acid addition of 1,3-diazaspiro [4.4] non-1-eno-4-one,  water and a base, preferably an inorganic base, even more preferably, KOH. The base is present in an amount between about 1 and about 6 molar equivalents with regarding the number of moles of acid salt 1,3-diazaspiro [4.4] non-1-eno-4-one.

The first and second solutions are combined to form a reaction system (mixture) that presents the First and second phases. The combination can be in any suitable container that is provided with stirring means intense reaction system to maximize the interfacial area Between the two phases. The combination can be to any temperature from about 20 ° C to about 95 ° C, preferably at about 90 ° C. The reaction is left to continue in the two-phase system for a time that the subject matter expert will know to adjust according to the reaction temperature When the reaction temperature is about 90 ° C, a reaction time between about 1 and about 2 hours is usually enough.

After the reaction time, the system reaction is allowed to cool, the two phases are separated. If desired, the aqueous phase can be extracted one or more times with toluene and the extract (s) combine with the first phase (aromatic hydrocarbon). The first phase is evaporated to obtain the raw waste

The present invention can be illustrated in one of their embodiments by the non-limiting example next.

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Example IA

IRB-05 Preparation

4

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To a preheated solution (90 ° C) of 4-bromobenzyl bromide and phase transfer catalyst
(Bu 4 NHSO 4) in toluene was added a pre-agitated solution (40 min. At room temperature) of KOH and IRB-01 in water. The resulting two-phase mixture was heated for 1 hour at 90 ° C with intense stirring. The mixture was cooled to room temperature, water (500 ml) was added and the mixture was stirred for 30 min. additional. The phases were separated and the aqueous phase was extracted with an additional portion of toluene (100 ml). The combined organic portions were washed with water and brine, dried over Na2SO4 and evaporated under reduced pressure. 74.0 g of IRB-05 were obtained as a colorless oil. The yield was 100%, with a purity of 94%.

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Example 1 B

IRB-06 Preparation

5

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6

To a solution of 5-phenyl-1H-tetrazol and triethylamine in anhydrous THF was added, in one portion, chlorotriphenylmethane The reaction was slightly exothermic, approximately 40 ° C. The resulting suspension was stirred under argon. for 2 hours (control by TLC; Hex / EtOAc 4: 1). The mixture is cooled to 0 ° C, stirred for 30 min. and the chloride was filtered from precipitated triethylammonium and washed with cold THF (100 ml). Be evaporated the filtrate under reduced pressure and the residue crystallized yellow solid (approximately 180 g) in acetonitrile (800 ml) to give 141.5 g. The yield was 94%, with a 94% purity.

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Example 1 C

Acid preparation 2- (5- (1-Trityl-1H-tetrazol) phenylboric

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7

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The solution of 5-phenyl-1-trityl-1H-tetrazol (IRB-06) in anhydrous THF (prepared in Example 1 B). The traces of water cooled with n-butyllithium (approximately 5 ml) When the mixture remained red for 5 minutes it interrupted the addition. The main load of n-butyllithium was added to then drop by drop at a temperature below -15 ° C and the resulting red suspension was stirred for an additional 30 minutes at -20 ° C. The mixture was cooled to -30 ° C, and borate was slowly added of triisopropyl, with the reaction temperature maintained by below -20 ° C. At this point, the slurry and solution were dissolved  resulting red was stirred for 30 minutes at -25 ° C, and at It was then heated at room temperature for 40 minutes. The solvents were evaporated under reduced pressure and the residue Semi-solid yellow was extracted with isopropyl alcohol (IPA) (200 ml) and cooled to 0 ° C. Aqueous NH4Cl was added slowly saturated (40 ml, approximately 180 mmol), maintaining the temperature below 10 ° C, and the boric acid suspension is Heated to room temperature. Water (160 ml) was added for 20 minutes and the resulting suspension was stirred for 2 hours at room temperature. The solid was filtered, washed with IPA / H 2 O / Et 3 N 50: 50: 2 (2 x 50 ml) and dried at reduced pressure at 40 ° C to constant weight to give 47.0 g of IRB-07 as solvate THF-H 2 O 1: 0.5 (dirty white solid) that was used without purifications additional. The yield was 92%, with a purity of 94.5%

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Example 1D

Preparation of 2-Butyl-3- [2 '- (triphenylmethyltetrazol-5-yl) -biphenyl-4-yl-methyl] -1,3-diazaspiro [4.4] non-1-eno-4-one  (IRB-03)

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A mixture of DME and THF was degassed by vacuum / nitrogen purges (3 times) and Ph 3 P was added in one portion. After the triphenylphosphine had dissolved, Pd (OAc) 2 was added, and the yellow-greenish mixture was degassed again (twice) and stirred for 30 min. at room temperature. IRB-07 was suspended, and stirring was continued for 10 min. at room temperature. Water was added, and the slurry was stirred for 30 min. additional. K2CO3 powder and IRB-05 were then successively added and the resulting mixture was degassed (3 times) and heated at reflux (approximately 80 ° C) for 3 hours (TLC control: Hex / EtOAc 2 :one). The solvents were evaporated under reduced pressure and toluene (20 ml) and water (20 ml) were added. After separation, the aqueous phase was extracted with toluene (10 ml) and the combined organic phases were washed with water and brine, dried over Na2SO4 and evaporated under reduced pressure to give 2.1 g. of the semi-solid residue. The crude material was crystallized from IPA (15 ml) to give 1.6 g of IRB-03 as a white solid. The yield was 90%, with a purity of
98%

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Example 1E

Preparation of irbesartan (IRB-00)

9

IRB-03 (produced in Example 1D) in acetone and 3N HCl and stirred for 2 hours at room temperature (control by TLC or HPLC). Slowly added a solution of KOH in 3 ml of water and the acetone was evaporated at reduced pressure The precipitate was filtered (trityl alcohol) and washed with water (2 x 5 ml). The combined aqueous filtrate is washed with 5 ml of ethyl acetate and slowly acidified to pH 4 with 3 N aqueous HCl. The resulting suspension was cooled between 0 and 4 ° C, stirred for 30 min. additional and leaked. He washed the cake several times with water and dried under reduced pressure between 50 and 60 ° C The yield was 0.58 g of IRB-00.

Claims (26)

1. Procedure for preparing 2-Butyl-3- [2 '- (1-triphenylmethyl-1H-tetrazol-5-yl) -biphenyl-4-yl] methyl] -1,3-diazaspiro [4.4] non-1-eno-4-one ,  which includes the stage of reacting 2-butyl-3- (4-bromobenzyl) -1,3-diazaspiro [4.4] non-1-eno-4-one  with the acid 2 - ((1-trityl-1H-tetrazol-5-yl)) phenylboronic in a solvent system comprising the first and second solvents in the presence of a catalyst. 2. Method according to claim 1, in which the catalyst is selected from the group constituted by palladium complexes and nickel complexes. 3. Method according to claim 2, in which the catalyst comprises a combination of a complex of palladium and a triaryl phosphine. 4. Method according to claim 3, in which the palladium complex is Pd (OAc) 2 and the Triaryl phosphine is triphenyl phosphine. 5. Procedure according to any of the claims 1, 2, 3 or 4, wherein the first solvent is select from the group consisting of ethers, formal, hydrocarbons, tetralins and mixtures thereof. 6. Method according to claim 5, in which the first solvent is selected from the group consisting of dimethoxyethane (DME), diethoxymethane, (diethyl formal), tetrahydrofuran, toluene, m-xylene and o-xylene. 7. Method according to claim 6, in which the first solvent is a mixture of dimethoxyethane and tetrahydrofuran. 8. Method according to claim 7, in the ratio of dimethoxyethane to tetrahydrofuran is about 10: 1 to about 1: 5 on a basis of volume. 9. Method according to claim 8, in the ratio of dimethoxyethane to tetrahydrofuran is about 6: 1 to about 2: 1 on a basis of volume. 10. Procedure according to any of the claims 1, 2, 3, 4, 5, 6, 7, 8 or 9, wherein the second Solvent comprises water and an inorganic base. 11. Method according to claim 10, in which inorganic base is potassium carbonate. 12. Procedure according to any of the claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11, wherein the reaction is at approximately reflux for a reaction time from about 2 hours to about 4 hours. 13. Method according to claim 1, which it also comprises a stage in which the trityl group is cleaved of the tetrazole ring of the 2-Butyl-3- [2 '- (1-triphenylmethyl-1H-tetrazol-5-yl) biphenyl-4-yl] methyl] 1,3-diazaspiro [4.4] non-1-eno-4-one  to produce irbesartan. 14. Procedure for preparing a compound from 3- (bromobenzyl) -1,3-diazaspiro [4.4] non-1-eno-4-one, which includes the stage consisting of: combine an acid addition salt of 1,3-diazaspiro [4.4] non-1-eno-4-one with a bromobenzyl halide in a two phase solvent system comprising first and second solvents, in the presence of a phase transfer catalyst. 15. Method according to claim 14, in which the acid addition salt of 1,3-diazaspiro [4.4] non-1-eno-4-one  is the hydrochloride of 2-butyl-1,3-diazaspiro [4.4] -1-eno-4-one and the compound of 3- (bromobenzyl) -1,3-diazaspiro [4.4] non-1-eno-4-one  is 2-butyl-3- (4'-bromobenzyl) -1,3-diazaspiro [4.4] non-1-eno-4-one. 16. Method according to claim 14, in which the acid addition salt of 1,3-diazaspiro [4.4] non-1-eno-4-one  It is in combination with salt water and a base. 17. Method according to claim 14, in which bromobenzyl halide is in combination with toluene and a phase transfer catalyst. 18. Method according to claim 17, in which bromobenzyl halide is the bromide of 4-bromobenzyl. 19. Method according to claim 16, in which inorganic base is KOH. 20. Method according to claim 14, in which the phase transfer catalyst is selected from between the group consisting of quaternary ammonium compounds and phosphonium compounds

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21. Method according to claim 20, in which the phase transfer catalyst is bisulfate of tetrabutylammonium 22. Method according to claim 14, in which the combination is at a temperature from about 20 ° C to about 95 ° C. 23. Method according to claim 22, in The temperature is approximately 90 ° C. 24. 2-butyl-3- (4'-bromobenzyl) -1,3-diazaspiro [4.4] non-1-eno-4-one. 25. Procedure for the preparation of Irbesartan, which comprises the following stages:

to)

combine the 5-phenyl-1H-tetrazol with chlorotriphenylmethane in the presence of THF and triethylamine;

b)

combine the product of step (a) with a borate, in the presence of THF and butyllithium;

C)

recover acid 2- (5-tetrazoyl) phenylboronic;

d)

combine the acid addition salt of 2-butyl-1,3-diazaspiro [4.4] non-1-eno-4-one with a 4-bromobenzyl bromide in a system solvent comprising the first and second solvents, in which the first solvent is a mixture of salt water and KOH, and the second solvent is toluene mixed with a catalyst of phase transfer selected from the constituted group by quaternary ammonium compounds and compounds of phosphonium;

and)

separate the two phases obtained;

F)

retrieve the 2-butyl-3- (4'-bromobenzyl) -1,3-diazaspiro [4.4] non-1-eno-4-one;

g)

do react the product recovered in step (c) with the product recovered in step (f) in a two phase solvent system comprising first and second solvents, in the presence of a catalyst, in which the first solvent is selected from the group consisting of ethers, formal, hydrocarbons, tetralins or mixtures thereof, and the second solvent it comprises water and potassium carbonate, and in which the catalyst is select from the group consisting of a palladium complex and a nickel complex;

h)

separate the two phases obtained;

i)

retrieve the 2-butyl-3- [2 '- (triphenylmethyltetrazol-5-yl) biphenyl-4-yl-methyl] -1,3-diazaspiro [4.4] non-1-eno-4-one;

j)

dissolve the product of step (i) in acetone;

k)

acidify the solution;

l)

neutralize the solution and separate the tritylic alcohol, thus obtaining a second solution;

m)

acidify the second solution;

n)

cool the second solution acidified; Y

or)

recover irbesartan.

26. Procedure for the preparation of Irbesartan, which comprises the following stages: react an acid addition salt of 2-butyl-1,3-diazaspiro [4.4] non-1-eno-4-one with 4-bromobenzyl bromide in a system two-phase solvent that has a first organic phase and a second aqueous phase in the presence of an inorganic base, thus obtaining the 2-butyl-3- (4'-bromobenzyl) -1,3-diazaspiro [4.4] non-1-eno-4-one,  and convert the 2-butyl-3- (4'-bromobenzyl) -1,3-diazaspiro [4.4] non-1-eno-4-one in irbesartan making it react with acid 2- (1-Trityl-1H-tetrazol-5-yl) phenylboronic and then cleaving the trityl group from the ring of tetrazole